The vision of routine whole genome resequencing for human genomics research and ultimately medicine is at the same time filled with immeasurable promise and daunting technical and conceptual challenges. The model organism Drosophila melanogaster has and continues to play a vibrant critical role in the advancement of methods and ideas used to understand variation in the structure and function of animal genomes. Recently released high-throughput sequencing platforms offer the first step on the path to the $1000 (or even $100) human genome. The early applications of these technologies already focus our attention on the enormous computational and analytic challenges of moving such vast genomic sequencing capacity to every laboratory. This proposal is an attempt to directly and creatively address these challenges by integrating the new high-throughput sequencing platforms with cutting-edge, small-footprint supercomputing to provide a large population sample (>1000) of sequenced genomes and their associated stocks to the imaginative and energetic Drosophila research community. To create this unique resource an efficient cluster of three high-throughput sequencing instruments will be integrated with four small-footprint, modular (FPGA-based) high performance computers that can support both the development of advance methods and the production of high quality syntenic assemblies. The availability of such large numbers of carefully sampled and sequenced Drosophila genomes will stimulate the population genetics research community to begin to address the fundamental mechanistic forces that shape variation among individual at a truly genomic scale. PUBLIC HEALTH RELEVANCE The goal of this project is to advance the technology and analytic methods for understanding genomic variation in populations by integrating benchtop supercomputing with ultra high- throughput resequencing to characterize a large sample of genomes of the fruitfly, Drosophila melanogaster. The envisioned rapid advance in the model organism system will provide essential ideas and talent to human population genomics research.